JAK inhibitors and monoclonal antibodies for the treatment of atopic dermatitis: effectiveness and value

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Agboola, Herron-Smith, Nhan, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Atlas, Brouwer, Carlson, and Hansen received funding from ICER for the work described in this summary.

Atopic dermatitis is a chronic and relapsing inflammatory skin condition characterized by itching and dry skin. It frequently begins during childhood and persists into adulthood in about half of affected children. 1 In the United States, atopic dermatitis is estimated to affect about 11%-15% of children and 7%-10% of adults. [2][3][4][5] Although the symptoms of atopic dermatitis vary in their severity, severe itching often disrupts sleep, leading to daytime tiredness, psychological stress, and impaired performance at school and work. [6][7][8] Furthermore, the aesthetic effect of chronic atopic dermatitis can lead to social stress and isolation. The overall US costs associated with atopic dermatitis are estimated to be $5.3 billion, including over $1 billion in health care costs. 9,10 Disease severity is difficult to characterize because it depends on the amount and location of skin involved, its appearance, and the subjective effect of symptoms. However, epidemiologic studies have reported that most children with atopic dermatitis have mild disease, with approximately 12%-26% having moderate disease and 4%-7% having severe disease. 1,11,12 There is less evidence on the severity of disease in adults; however, the moderate to severe form of the disease appears to be more common in adults. 13 Treatment strategies for atopic dermatitis include hydration with moisturizers and emollients, shortterm intermittent treatment with topical corticosteroids, and long-term maintenance with topical calcineurin inhibitors or crisaborole. 14 For those with atopic dermatitis not controlled with topical therapies, phototherapy or general systemic immunomodulators, such as cyclosporine and azathioprine, are used. 15 In addition, dupilumab, an IL-4 receptor antagonist that became available in the United States in 2017 as the first approved biologic treatment for atopic dermatitis, is now a commonly used systemic immunomodulator for moderate to severe disease. 16 There are several emerging treatments that are expected to play important roles in therapy. Tralokinumab is an IL-13 receptor antagonist currently under US Food and Drug Administration (FDA) review for patients with moderate to severe atopic dermatitis. Similar to dupilumab, tralokinumab is given subcutaneously. In addition, ruxolitinib cream, a topical janus kinase (JAK) inhibitor, was recently approved by the FDA for patients with mild to moderate atopic dermatitis. Oral JAK inhibitors abrocitinib, baricitinib, and upadacitinib are also being evaluated for patients with moderate to severe atopic dermatitis, but the FDA has extended the review period for these drugs because of recent data that JAK inhibitors and monoclonal antibodies for the treatment of atopic dermatitis: effectiveness and value have raised questions about the safety of oral JAK inhibitors approved for other conditions. 17 The Institute for Clinical and Economic Review (ICER) evaluated tralokinumab, abrocitinib, baricitinib, upadacitinib, and ruxolitinib cream for atopic dermatitis. This report presents the summary of our systematic literature review and cost-effectiveness analysis and highlights the key policy recommendations discussed at the New England Comparative Effectiveness Public Advisory Council's public meeting on July 23, 2021. The detailed report is available at https://icer.org/wp-content/ uploads/2020/12/Atopic-Dermatitis_ Final-Evidence-Report_081721.pdf.

Summary of Findings
We evaluated the clinical effectiveness of tralokinumab and the 3 oral JAK inhibitors (abrocitinib, baricitinib, and upadacitinib) vs placebo and vs dupilumab in patients with moderate to severe atopic dermatitis. In addition, we examined the clinical effectiveness abrocitinib and upadacitinib appeared to have similar outcomes compared with adults.
Using a Bayesian network metaanalysis (NMA), we combined outcome data from all eligible monotherapy RCTs to indirectly compare the interventions to each other. Similar to what was observed in the head-to-head trials, the NMA suggests that the higher doses of abrocitinib and upadacitinib were similar or better than dupilumab. For example, compared with dupilumab, relative risks (RR) for achieving at least a 75% reduction in the Eczema Area and Severity Index (EASI 75) were 1.20 (95% credible interval [CrI] = 0.97-1.46) and 1.38 (95% CrI = 1.23-1.56) for abrocitinib 200 mg and updacitinib 30 mg, respectively. In contrast, dupilumab was significantly better than tralokinumab (RR = 1.58; 95% CrI = 1.25-2.03) and both doses of baricitinib (higher dose, RR = 1.64; 95% CrI = 1.28-2.15) on EASI 75 (and other main outcomes); however, there is substantial uncertainty in these comparisons because of the lack of head-to-head evidence. Based on the NMA, the expected proportion of patients who achieved different EASI thresholds is presented in Table 1.
Most adverse events (AEs) observed in the trials were of mild to moderate severity. The most commonly reported AEs with greater incidence than placebo were nausea, conjunctivitis, and herpetic infection. The incidence of discontinuation due to AEs and serious AEs were low and generally similar among these agents. However, evidence from trials evaluating JAK inhibitors at longer time points for other indications suggests an increased risk of serious AEs, such as reactivation of herpes zoster, malignancy, thromboembolic events, and cardiovascular events 36 ; this has led the FDA to place black box warnings of ruxolitinib cream in patients with mild to moderate atopic dermatitis.
Abrocitinib, baricitinib, tralokinumab, and upadacitinib all improved skin outcomes compared with placebo, and, where assessed, appeared to improve itch, sleep, and quality of life for patients with moderate to severe atopic dermatitis. The few adolescent patients included in the trials of  TABLE 1 from a US health care sector perspective using an adapted Markov model previously developed for dupilumab. 37 We did not evaluate the cost-effectiveness of ruxolitinib cream. The Markov model was developed with health states based on treatment response measured by EASI scores. 38 Health states were categorized by the percent decrease in EASI score from baseline after a patient begins an intervention: less than 50% decrease (no response), 50%-74% decrease (EASI 50), 75%-89% decrease (EASI 75), and 90%-99% decrease (EASI 90). Costs and outcomes were discounted at an annual rate of 3% over a 5-year time horizon.

Proportions of Patients Achieving EASI Thresholds as Estimated From Bayesian Network Meta-Analysis
The model was informed by the results of the ICER NMA previously described, before relevant economic models, other published studies on atopic dermatitis, and stakeholder input, including manufacturer-submitted data. 37,39 At the time of the report, there were no available prices for abrocitinib and tralokinumab, so we used placeholder prices to generate cost-effectiveness results. For abrocitinib, we used the average of the net prices of baricitinib and upadacitinib. For tralokinumab, the net price of dupilumab was used as the placeholder price. Full details on ICER's cost-effectiveness analysis and model are available on ICER's website at https://icer.org/wp-content/ uploads/2020/12/Atopic-Dermatitis_ Final-Evidence-Report_081721.pdf.
Results from our analysis showed that when compared with standard of care, the incremental cost-effectiveness ratio was lowest for baricitinib at $71,600 per quality-adjusted life-year (QALY) and highest for upadacitinib at $248,400 per QALY. QALY results are identical to those using equal value of life-years gained (evLYG), given that these treatments are not expected to extend life. Compared with dupilumab, model results showed that

LIMITATIONS OF THE CLINICAL EVIDENCE
Tralokinumab and JAK inhibitors are therapies with novel mechanisms of action affecting the body's immune system, and we lack long-term safety data for patients with atopic dermatitis. In addition, due to the limited head-to-head data on these agents, we used indirect analyses to compare abrocitinib, baricitinib, tralokinumab, and upadacitinib with each other and to dupilumab. However, the results of indirect analyses are more uncertain than when the therapies are compared directly. Finally, there is limited information available about the relative benefits and harms of these new therapies in important subgroups, particularly among adolescents aged 12-17 years and African-Americans, given the significant effect of atopic dermatitis in these subgroups.

LONG-TERM COST-EFFECTIVENESS
We evaluated the cost-effectiveness of abrocitinib, baricitinib, tralokinumab, and upadacitinib vs standard of care and vs dupilumab in adult patients with moderate to severe atopic dermatitis on this class of agents and has delayed the approval of these agents for atopic dermatitis.
In the mild to moderate population, topical ruxolitinib cream was significantly better than vehicle cream (placebo) on all skin and patient-reported outcomes in 2 RCTs. Even though ruxolitinib cream also appeared to be more effective than a medium potency topical corticosteroid, it was not compared with more potent topical corticosteroids, and differences in trial designs precluded indirect quantitative comparisons across topical therapies. The most commonly reported AEs included application site burning and pruritus, and the incidence of these AEs was lower in the ruxolitinib cream arms than placebo arm. As a topical JAK inhibitor therapy, safety concerns are likely not as great as with oral JAK inhibitors; however, its FDA approval came with the same black box warnings seen for other JAK inhibitors, highlighting the risk of serious infections malignancies and serious cardiovascular-related events.

Policy Discussion
The New England Comparative Effectiveness Public Advisory Council (CEPAC) convened on July 23, 2021, to publicly deliberate on the clinical and cost-effectiveness of treatments of atopic dermatitis. The New England CEPAC is an independent appraisal committee composed of medical evidence experts, including practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Their deliberation included input from clinical experts and patient representatives with atopic dermatitis expertise and formal comments from manufacturers and the public. Following the discussion, the CEPAC members deliberated on key questions raised by ICER's report. Based on the evidence in the clinical trials and ongoing concerns baricitinib and tralokinumab were both less costly and less effective. Abrocitinib and upadacitinib had incremental cost-effectiveness ratios of approximately $300,000 and $1.9 million per QALY, respectively. Detailed results are presented in Table 2.

LIMITATIONS OF THE COST-EFFECTIVENESS MODEL
The clinical trial efficacy was extrapolated beyond the length of the trials, which assumes continued effectiveness and adherence to treatment. Additionally, the model assumes that levels of EASI response are the primary driver of differences in health-related quality of life; however, the treatments may have differential effects on itch and sleep that vary in their correlation with EASI response scores. There may also be incremental effects of these treatments  Recommendation: If multiple agents for severe atopic dermatitis are approved, payers should make available at least 1 biologic (dupilumab and/or tralokinumab) and at least 1 JAK inhibitor, given how different these classes are in their onset of action and their risk profile.
Recommendation: Manufacturers should establish long-term registries that can be used to assess the benefits and harms of chronic use of oral JAK inhibitors for patients with atopic dermatitis. There are potentially serious risks and adverse events associated with JAK inhibitors, so long-term follow-up is warranted. from insurers and manufacturers joined clinical experts and patient representatives and discussed how best to apply the evidence and additional considerations into clinical practice and pricing and insurance coverage policies. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website.

DISCLOSURES
The key policy recommendations are as follows: Recommendation: All stakeholders have a responsibility and an important role in ensuring that effective new treatment options for patients with atopic dermatitis are introduced in a way that will help reduce health inequities.
Recommendation: Some considerations for prior authorizations: Patient eligibility: Age criteria are likely to follow the FDA label, so payers should have efficient mechanisms for clinicians to seek coverage exceptions for patients with serious unmet needs near the cutoff for the age necessary for coverage.
Clinical eligibility: Given the lack of clear consensus on how "moderate to severe" atopic dermatitis is defined, payers should operationalize the definition/measure of disease severity so that it is kept broad, is inclusive of multiple measures of disease intensity, and is clinically relevant for clinicians.
Duration of coverage and renewal criteria: Payers should establish an initial coverage period of 6-12 months, which is long enough for dose titration, assessment of side effects, or disease progression.
Recommendation: Payers should only use step therapy when it provides adequate flexibility to meet the needs of diverse patients and when the implementation can meet high standards of transparency and efficiency. For example, payers establishing step therapy with less expensive systemic agents and/or phototherapy should about long-term safety with oral JAK inhibitors, the panel votes were split as to the net health benefit of adding abrocitinib , baricitinib , and upadacitinib (9-4) to usual care compared with usual care alone. The panel voted 11-2 that the clinical evidence was adequate to demonstrate a greater net health benefit for tralokinumab plus usual care compared with usual care alone. Finally, the panel voted 12-1 that the clinical evidence was adequate to demonstrate a greater net health benefit for ruxolitinib cream plus usual care compared with usual care alone in mild to moderate atopic dermatitis.
The CEPAC panel also voted on "other potential benefits" and "contextual considerations" as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical and/or cost-effectiveness. The results of these votes are shown in Tables 3 and 4.
The culminating vote of the CEPAC panel, intended to reflect its integration of the relevant elements of the value assessment framework, was on the "long-term value for money." The panelists did not vote on abrocitinib and tralokinumab because prices were not available for these drugs at the time of the public meeting. However, baricitinib and upadacitinib have a known price, since they are approved for other indications. For baricitinib, the panel members voted that its long-term value for money is intermediate (7/13 votes) or high (6/13 votes) compared with usual care. The majority of the panel voted that upadacitinib represents a low value for money at the current price compared with usual care (10/13 votes).
The meeting concluded with a policy roundtable where representatives